FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2014235008> ?p ?o ?g. }

• W2014235008 endingPage "1668" @default.
• W2014235008 startingPage "1666" @default.
• W2014235008 abstract "Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, autosomal recessive, primary immunodeficiency characterized by fever, hepatosplenomegaly, and systemic inflammatory response syndrome. It is associated with pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and tissue infiltration by activated macrophages and hematophagocytes. It is rapidly fatal if untreated.1Filipovich A.H. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders.Immunol Allergy Clin North Am. 2008; 28 (viii): 293-313Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) include the presence of a disease-causing mutation and/or at least 5 of the following 8 clinical criteria: prolonged fever (>7 days), cytopenias affecting 2 or more peripheral blood cell lineages, splenomegaly, hypertriglyceridemia and/or hypofibrinogenemia, hemophagocytosis, low or absent natural killer (NK) cell activity, hyperferritinemia, and elevated plasma sIL2Rα.2Henter J.I. Horne A. Aricó M. Egeler R.M. Filipovich A.H. Imashuku S. et al.HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.Pediatr Blood Cancer. 2007; 48: 124-131Crossref PubMed Scopus (3172) Google Scholar FHL results from defective cytolytic function leading to an inability to appropriately regulate and contain certain immune responses.1Filipovich A.H. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders.Immunol Allergy Clin North Am. 2008; 28 (viii): 293-313Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 3Orange J.S. Formation and function of the lytic NK-cell immunological synapse.Nat Rev Immunol. 2008; 8: 713-725Crossref PubMed Scopus (404) Google Scholar As a result, there is excessive cytokine production and macrophage activation. FHL-causing mutations occur in the genes encoding perforin (PRF1 and FHL2), Munc13-4 (UNC13D and FHL3), syntaxin-11 (STX11 and FHL4), and Munc18-2 (STXBP2 and FHL5).4zur Stadt U. Rohr J. Seifert W. Koch F. Grieve S. Pagel J. et al.Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.Am J Hum Genet. 2009; 85: 482-492Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 5Zur Stadt U. Beutel K. Kolberg S. Schneppenheim R. Kabisch H. Janka G. et al.Mutation spectrum in children with primary hemophagocytic lymphohistiocytosis: molecular and functional analyses of PRF1, UNC13D, STX11, and RAB27A.Hum Mutat. 2006; 27: 62-68Crossref PubMed Scopus (234) Google Scholar All impair the ability of cytotoxic lymphocytes, including NK cells and cytotoxic T lymphocytes, to secrete lytic effector molecules normally contained within specialized lysosomal organelles called lytic granules.1Filipovich A.H. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders.Immunol Allergy Clin North Am. 2008; 28 (viii): 293-313Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar, 3Orange J.S. Formation and function of the lytic NK-cell immunological synapse.Nat Rev Immunol. 2008; 8: 713-725Crossref PubMed Scopus (404) Google Scholar Cytotoxic lymphocytes function to recognize and destroy infected or malignant cells, and their role in FHL represents a new understanding as to how they function to maintain normal immunity. The most recently described form of FHL (FHL5) results from mutation of the STXBP2 gene encoding syntaxin-binding protein 2 (also known as Munc18-2). Munc18-2 interacts with syntaxin-11, a soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) protein, and together they enable fusion of the lytic granule membrane with that of the cytotoxic lymphocyte to promote degranulation. Mutations in FLH5 abrogate the interaction between Munc18-2 and syntaxin-11 and prevent this necessary prerequisite step for cytotoxicity. Although in FHL5, NK cells are able to conjugate with and polarize lytic granules toward the target cell, they are unable to release their granule contents.6Côte M. Ménager M.M. Burgess A. Mahlaoui N. Picard C. Schaffner C. et al.Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.J Clin Invest. 2009; 119: 3765-3773Crossref PubMed Scopus (280) Google Scholar Thus, there is reduced activity of NK and cytotoxic T cells (the former being more pronounced in FHL5 for reasons that are presently unclear).4zur Stadt U. Rohr J. Seifert W. Koch F. Grieve S. Pagel J. et al.Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.Am J Hum Genet. 2009; 85: 482-492Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 6Côte M. Ménager M.M. Burgess A. Mahlaoui N. Picard C. Schaffner C. et al.Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.J Clin Invest. 2009; 119: 3765-3773Crossref PubMed Scopus (280) Google Scholar, 7Meeths M. Entesarian M. Al-Herz W. Chiang S.C. Wood S.M. Al-Ateeqi W. et al.Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.Blood. 2010; 116: 2635-2643Crossref PubMed Scopus (94) Google Scholar, 8Cetica V. Santoro A. Gilmour K.C. Sieni E. Beutel K. Pende D. et al.STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.J Med Genet. 2010; 47: 595-600Crossref PubMed Scopus (42) Google Scholar Previous in vitro studies with FHL5 patient cells have demonstrated that the defect in NK cell cytotoxicity can be partially restored after short-term in vitro exposure to the stimulatory cytokine IL-2.4zur Stadt U. Rohr J. Seifert W. Koch F. Grieve S. Pagel J. et al.Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.Am J Hum Genet. 2009; 85: 482-492Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 6Côte M. Ménager M.M. Burgess A. Mahlaoui N. Picard C. Schaffner C. et al.Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.J Clin Invest. 2009; 119: 3765-3773Crossref PubMed Scopus (280) Google Scholar, 7Meeths M. Entesarian M. Al-Herz W. Chiang S.C. Wood S.M. Al-Ateeqi W. et al.Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.Blood. 2010; 116: 2635-2643Crossref PubMed Scopus (94) Google Scholar, 8Cetica V. Santoro A. Gilmour K.C. Sieni E. Beutel K. Pende D. et al.STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.J Med Genet. 2010; 47: 595-600Crossref PubMed Scopus (42) Google Scholar This implies the existence of a Munc18-2–independent pathway to access SNARE function. It also suggests the potential for therapeutic intervention to restore NK cell function in FHL5. We present the case of 19-month-old dizygotic twins with FHL5, in which we studied the NK cell cytolytic function in consideration of expanded FHL5 phenotypes. The index patient had an unremarkable medical history and was born to nonrelated Ashkenazi Jewish parents. At 19 months, he had 2 weeks of fever (Tmax, 105°F), during which time his twin brother had been diagnosed with an upper respiratory tract infection. On presentation, the index patient was febrile and ill-appearing with exudative tonsillar hypertrophy, diffuse cervical lymphadenopathy, hepatosplenomegaly, and bilateral pedal edema (clinical laboratory data: white blood cell count, 36,500/μL with 53% atypical lymphocytes; hemoglobin, 10.3 g/dL; platelets, 214,000/μL; alanine aminotransferase, 440 U/L; aspartate aminotransferase, 312 U/L; ferritin, 807 ng/mL; trigylcerides, 494 mg/dL; sIL2Rα, 25,409 U/mL). Bone marrow examination demonstrated diffuse hematophagocytes (Fig 1, A). Both the index patient and his twin were found to have novel biallelic mutations for Munc18-2 [474_483 del_insGA/1001 C>T (P334L)] (Fig 1, B). They did not have mutations in the other known genes responsible for FHL or X-linked lymphoproliferative syndrome. The index patient fulfilled 8 of 8 HLH diagnostic criteria,2Henter J.I. Horne A. Aricó M. Egeler R.M. Filipovich A.H. Imashuku S. et al.HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.Pediatr Blood Cancer. 2007; 48: 124-131Crossref PubMed Scopus (3172) Google Scholar while his twin brother remained asymptomatic. PCR-based sequencing of the STXBP2 gene in 329 unrelated patients diagnosed with HLH yielded biallelic STXBP2 mutations in 32 unrelated families and 22 additional heterozygous mutations and sequence variants. None of these, however, shared our patient’s mutations. Informed consent was obtained for record review and experimental studies using a protocol approved by The Children’s Hospital of Philadelphia Institutional Review Board for the protection of human subjects. For experimental studies of NK cell functions, PBMCs were prepared and cytotoxicity was assessed by using 4-hour 51Cr release assays against labeled K562 erythroleukemia cells, 721.221 EBV-transformed B cells, or Raji B cells as described.9Orange J.S. Roy-Ghanta S. Mace E.M. Maru S. Rak G.D. Sanborn K.B. et al.IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.J Clin Invest. 2011; 121: 1535-1548Crossref PubMed Scopus (66) Google Scholar Short-term IL-2 stimulation was performed by adding 1000 IU/mL human recombinant IL-2 (National Institutes of Health AIDS reagent program), while antibody-dependent cellular cytotoxicity was determined by the addition of monoclonal anti-CD20 (rituximab; Genentech Inc, San Francisco, Calif) at 20 μg/mL to the 4-hour assay against Raji B target cells (which were not lysed without added antibody; data not shown). All assays were repeated at least twice by using independent blood samples. Our symptomatic patient as well his asymptomatic brother had defective NK cell cytotoxicity against the canonical NK cell target cell line, K562 erythroleukemia cells (Fig 2, A). In contrast to reported results, however, both affected individuals, but not their parents or a control, failed to respond to IL-2 with an increase in NK cell cytotoxicity (Fig 2, B). To ensure that the IL-2–resistant decreased NK cell function in the patients was not specific to the target cells used, we also evaluated an EBV-transformed B-cell target cell (Fig 2, C). Here we found that the NK cell cytotoxic activity of the 2 brothers was deficient and could not be enhanced by short-term IL-2 exposure. To ensure that the deficient NK cell function was not a feature of particular receptors, we also evaluated antibody-dependent cellular cytotoxicity, which has not been previously studied in FHL5. The antibody-dependent cellular cytotoxicity of the brothers, but not their parents, was absent (Fig 2, D). In all cases, the Munc18-2 mutant heterozygous parents were similar in cytolytic function, and less than that of the control. Prior studies have shown that the deficient cytotoxicity in patients with FHL5 can be reversed after short-term in vitro exposure of PBMCs to IL-2.4zur Stadt U. Rohr J. Seifert W. Koch F. Grieve S. Pagel J. et al.Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.Am J Hum Genet. 2009; 85: 482-492Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 6Côte M. Ménager M.M. Burgess A. Mahlaoui N. Picard C. Schaffner C. et al.Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.J Clin Invest. 2009; 119: 3765-3773Crossref PubMed Scopus (280) Google Scholar, 7Meeths M. Entesarian M. Al-Herz W. Chiang S.C. Wood S.M. Al-Ateeqi W. et al.Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.Blood. 2010; 116: 2635-2643Crossref PubMed Scopus (94) Google Scholar, 8Cetica V. Santoro A. Gilmour K.C. Sieni E. Beutel K. Pende D. et al.STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.J Med Genet. 2010; 47: 595-600Crossref PubMed Scopus (42) Google Scholar However, our data describe a novel STXBP2 mutation, which to our knowledge represents the first reported to have a fixed pervasive deficiency of NK cell cytotoxicity that does not respond to IL-2 stimulation. Given the complete and consistent lack of response to IL-2, it is thus unlikely that IL-2 is inducing a pathway to cytotoxicity truly independent of Munc18-2 (akin to what we have found in Wiskott-Aldrich syndrome, where IL-2 can circumvent WASp altogether).9Orange J.S. Roy-Ghanta S. Mace E.M. Maru S. Rak G.D. Sanborn K.B. et al.IL-2 induces a WAVE2-dependent pathway for actin reorganization that enables WASp-independent human NK cell function.J Clin Invest. 2011; 121: 1535-1548Crossref PubMed Scopus (66) Google Scholar Thus, we hypothesize that IL-2 is allowing for expanded access to function via a crippled STXBP2 gene or Munc18-2 protein. At present, the only curative option for patients with STXBP2 mutations in FHL5, as with other types of HLH, is hematopoietic stem cell transplantation.1Filipovich A.H. Hemophagocytic lymphohistiocytosis and other hemophagocytic disorders.Immunol Allergy Clin North Am. 2008; 28 (viii): 293-313Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar The index patient was transplanted with hematopoietic stem cells from a matched sibling donor facilitated by reduced intensity conditioning. He is presently doing well. His twin brother remains asymptomatic. It is unclear as to why he has not developed hematophagocytosis and speaks to potential modifying genetic influences not present in his affected brother. Given that IL-2 has been previously identified to induce NK cell cytotoxicity, it has been proposed as a potential adjunct or temporizing therapy for patients with FHL5.4zur Stadt U. Rohr J. Seifert W. Koch F. Grieve S. Pagel J. et al.Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11.Am J Hum Genet. 2009; 85: 482-492Abstract Full Text Full Text PDF PubMed Scopus (307) Google Scholar, 6Côte M. Ménager M.M. Burgess A. Mahlaoui N. Picard C. Schaffner C. et al.Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells.J Clin Invest. 2009; 119: 3765-3773Crossref PubMed Scopus (280) Google Scholar, 7Meeths M. Entesarian M. Al-Herz W. Chiang S.C. Wood S.M. Al-Ateeqi W. et al.Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2.Blood. 2010; 116: 2635-2643Crossref PubMed Scopus (94) Google Scholar, 8Cetica V. Santoro A. Gilmour K.C. Sieni E. Beutel K. Pende D. et al.STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5.J Med Genet. 2010; 47: 595-600Crossref PubMed Scopus (42) Google Scholar In light of our observations, further studies are needed to elucidate which syntaxin-11/Munc18-2 abnormalities can be augmented by IL-2 and certainly should at least prompt evaluation of the results of direct in vitro cytotoxicity testing before considering IL-2 therapeutically. Specifically, it may be effective for only a subset of patients with FHL5. We thank Dr Nancy Bunin (The Children’s Hospital of Philadelphia) for care of the index patient during the posttransplant process; Dr John Choi (The Children’s Hospital of Philadelphia) and Dr Daniela Mihova (University of Pennsylvania) for immunohistochemistry assistance; and the patients and their families for their assistance in this effort." @default.
• W2014235008 created "2016-06-24" @default.
• W2014235008 creator A5042675828 @default.
• W2014235008 creator A5052534306 @default.
• W2014235008 creator A5061601202 @default.
• W2014235008 creator A5068698149 @default.
• W2014235008 creator A5069051471 @default.
• W2014235008 creator A5080315304 @default.
• W2014235008 date "2012-06-01" @default.
• W2014235008 modified "2023-09-25" @default.
• W2014235008 title "Novel mutation in STXBP2 prevents IL-2–induced natural killer cell cytotoxicity" @default.
• W2014235008 cites W2006721905 @default.
• W2014235008 cites W2008416574 @default.
• W2014235008 cites W2018840153 @default.
• W2014235008 cites W2023392073 @default.
• W2014235008 cites W2046813237 @default.
• W2014235008 cites W2047164801 @default.
• W2014235008 cites W2054218102 @default.
• W2014235008 cites W2122970793 @default.
• W2014235008 cites W2162251899 @default.
• W2014235008 doi "https://doi.org/10.1016/j.jaci.2011.12.1003" @default.
• W2014235008 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/3646578" @default.
• W2014235008 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/22336081" @default.
• W2014235008 hasPublicationYear "2012" @default.
• W2014235008 type Work @default.
• W2014235008 sameAs 2014235008 @default.
• W2014235008 citedByCount "10" @default.
• W2014235008 countsByYear W20142350082013 @default.
• W2014235008 countsByYear W20142350082015 @default.
• W2014235008 countsByYear W20142350082016 @default.
• W2014235008 countsByYear W20142350082018 @default.
• W2014235008 countsByYear W20142350082019 @default.
• W2014235008 countsByYear W20142350082021 @default.
• W2014235008 countsByYear W20142350082022 @default.
• W2014235008 crossrefType "journal-article" @default.
• W2014235008 hasAuthorship W2014235008A5042675828 @default.
• W2014235008 hasAuthorship W2014235008A5052534306 @default.
• W2014235008 hasAuthorship W2014235008A5061601202 @default.
• W2014235008 hasAuthorship W2014235008A5068698149 @default.
• W2014235008 hasAuthorship W2014235008A5069051471 @default.
• W2014235008 hasAuthorship W2014235008A5080315304 @default.
• W2014235008 hasBestOaLocation W20142350081 @default.
• W2014235008 hasConcept C104317684 @default.
• W2014235008 hasConcept C109316439 @default.
• W2014235008 hasConcept C185592680 @default.
• W2014235008 hasConcept C202751555 @default.
• W2014235008 hasConcept C203014093 @default.
• W2014235008 hasConcept C2778102761 @default.
• W2014235008 hasConcept C2778690821 @default.
• W2014235008 hasConcept C501734568 @default.
• W2014235008 hasConcept C502942594 @default.
• W2014235008 hasConcept C54355233 @default.
• W2014235008 hasConcept C74172505 @default.
• W2014235008 hasConcept C86803240 @default.
• W2014235008 hasConcept C98119934 @default.
• W2014235008 hasConceptScore W2014235008C104317684 @default.
• W2014235008 hasConceptScore W2014235008C109316439 @default.
• W2014235008 hasConceptScore W2014235008C185592680 @default.
• W2014235008 hasConceptScore W2014235008C202751555 @default.
• W2014235008 hasConceptScore W2014235008C203014093 @default.
• W2014235008 hasConceptScore W2014235008C2778102761 @default.
• W2014235008 hasConceptScore W2014235008C2778690821 @default.
• W2014235008 hasConceptScore W2014235008C501734568 @default.
• W2014235008 hasConceptScore W2014235008C502942594 @default.
• W2014235008 hasConceptScore W2014235008C54355233 @default.
• W2014235008 hasConceptScore W2014235008C74172505 @default.
• W2014235008 hasConceptScore W2014235008C86803240 @default.
• W2014235008 hasConceptScore W2014235008C98119934 @default.
• W2014235008 hasFunder F4320306433 @default.
• W2014235008 hasFunder F4320307303 @default.
• W2014235008 hasFunder F4320308876 @default.
• W2014235008 hasFunder F4320332161 @default.
• W2014235008 hasIssue "6" @default.
• W2014235008 hasLocation W20142350081 @default.
• W2014235008 hasLocation W20142350082 @default.
• W2014235008 hasLocation W20142350083 @default.
• W2014235008 hasLocation W20142350084 @default.
• W2014235008 hasOpenAccess W2014235008 @default.
• W2014235008 hasPrimaryLocation W20142350081 @default.
• W2014235008 hasRelatedWork W1585161294 @default.
• W2014235008 hasRelatedWork W2014235008 @default.
• W2014235008 hasRelatedWork W2028235547 @default.
• W2014235008 hasRelatedWork W2039597599 @default.
• W2014235008 hasRelatedWork W2067963346 @default.
• W2014235008 hasRelatedWork W2355358775 @default.
• W2014235008 hasRelatedWork W2395493747 @default.
• W2014235008 hasRelatedWork W2409113266 @default.
• W2014235008 hasRelatedWork W2418656659 @default.
• W2014235008 hasRelatedWork W3131160141 @default.
• W2014235008 hasVolume "129" @default.
• W2014235008 isParatext "false" @default.
• W2014235008 isRetracted "false" @default.
• W2014235008 magId "2014235008" @default.
• W2014235008 workType "article" @default.